Project Summary While current antiretroviral (ART) therapies are able to control viral replication, they are unable to fully restore health or a normal immune status. ART-treated individuals still experience several co-morbidities including increased cardiovascular disease, bone disorders and cognitive impairment. Most importantly, therapy interruption leads to the re-emergence of viral replication and AIDS progression. Therefore, the development of new approaches aimed at eradicating or functionally curing HIV infection are desperately needed. Shock- and-kill strategies represent promising approaches to HIV eradication. However, latently infected cells in which viral production has been induced by latency-reversing agents are unlikely to be depleted in the absence of an efficient immune response. An alternative and perhaps more realistic approach to eliminate latently infected cells after viral reactivation relies on the ability of immune cells to mediate antibody-dependent cellular cytotoxicity (ADCC). Through ADCC, effector cells such as NK cells and monocytes can kill infected cells expressing the envelope glycoproteins (Env) through recognition by HIV-specific antibodies. Because the HIV- 1 Vpu and Nef proteins keep Env-CD4 complexes, the major target for ADCC, off the cell surface, this immune mechanism is naturally relatively inefficient. However, we recently discovered that CD4-mimetic compounds (CD4mc) are able to push the HIV-1 envelope glycoproteins (Env) to sample the CD4-bound conformation, resulting in sensitization of HIV-1-infected cells to ADCC. Our observations suggest that CD4mc could be useful for the kill part of the shock-and-kill strategy being pursued to purge the HIV reservoir, and thus could have therapeutic utility in decreasing the size of the viral reservoir upon reactivation. The objective of this proposal is to provide a proof of concept for the value of CD4mc in reducing the size of the viral reservoir in SHIV-infected rhesus macaques, which could expedite application to HIV-1-infected humans.